The loss of striatal doparninergic afferents underlies Parkinson's disease (PD). The changes that occur in response to striatal doparnine (DA) deafferentation have been the subject in intense scrutiny, with most efforts focusing on adaptive changes in the surviving DA neurons. However, changes in striatal medium spine neurons (MSNs) also occur. Among these are a decrease in dendritic spine density, which is seen in both experimentally-induced striatal DA denervation and late-stage PD. The changes in dendritic spines have been suggested to underlie a decreased responsiveness to DA replacement treatment late in the course of PD and possibly the development of dyskinesias. DA axons terminate onto the neck of dendritic spines of MSNs, with excitatory (glutamatergic) corticostriatal axons forming synapses onto the spine head. This triadic arrangement suggests that the loss of DA may result in decreased gating of excitatory inputs to the spine, culminating in the loss of the dendritic spine. We will test the hypothesis that DA denervation results in a preferential loss of dendritic spines on striatopallidal neurons through a glutamate-dependent mechanism that leads to increased [Ca2+]i. We will first characterize the MSNs in: which DA denervation elicits dendritic spine loss, using both 6- hydroxydopamine and MPTP to disrupt the striatal DA innervation. These studies will focus on determining if MSNs that exhibit dendritic atrophy are in the striatal patch (striosome) or matrix compartments and if there is a preferential loss of dendritic spines in striatopallidal neurons. We will then determine if the loss of DA signaling through D2 or D1 receptors subserves the decreased spine density, using both DA receptor knockout mice and animals treated chronically with DA receptor antagonists; the antagonist studies will also allow us to determine if changes in dendritic spines are reversible. The effects of chronic DA replacement (I-DOPA) treatment on the loss of dendritic spines will be assessed. Finally, we will determine if the change in glutamatergic drive onto MSNs results in dendritic changes through NMDA or AMPA receptors and measure the capacity of MSNs to buffer [Ca2+]i in response to NMDA or AMPA These studies will expand our understanding of the pathophysiology of PD and may open new approaches to the treatment of Parkinson's disease, particularly in slowing disease progression.